rs3027875

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_StrongBP7BA1

The ENST00000310441.12(HCFC1):c.5859C>T(p.Cys1953Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 111,874 control chromosomes in the GnomAD database, including 9,743 homozygotes. There are 13,393 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 9743 hom., 13393 hem., cov: 24)

Exomes 𝑓: 0.58 ( 136906 hom. 204100 hem. )

Failed GnomAD Quality Control

Consequence

HCFC1
ENST00000310441.12 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.400

Publications

11 publications found

Variant links:

Genes affected

HCFC1 (HGNC:4839): (host cell factor C1) This gene is a member of the host cell factor family and encodes a protein with five Kelch repeats, a fibronectin-like motif, and six HCF repeats, each of which contains a highly specific cleavage signal. This nuclear coactivator is proteolytically cleaved at one of the six possible sites, resulting in the creation of an N-terminal chain and the corresponding C-terminal chain. The final form of this protein consists of noncovalently bound N- and C-terminal chains. The protein is involved in control of the cell cycle and transcriptional regulation during herpes simplex virus infection. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

HCFC1 Gene-Disease associations (from GenCC):

methylmalonic acidemia with homocystinuria, type cblX
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, Illumina
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

HCFC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP6

Variant X-153950388-G-A is Benign according to our data. Variant chrX-153950388-G-A is described in ClinVar as Benign. ClinVar VariationId is 95281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.4 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000310441.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCFC1	NM_005334.3	MANE Select	c.5859C>T	p.Cys1953Cys	synonymous	Exon 24 of 26	NP_005325.2
HCFC1	NM_001440843.1		c.6000C>T	p.Cys2000Cys	synonymous	Exon 24 of 26	NP_001427772.1
HCFC1	NM_001410705.1		c.5994C>T	p.Cys1998Cys	synonymous	Exon 24 of 26	NP_001397634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCFC1	ENST00000310441.12	TSL:1 MANE Select	c.5859C>T	p.Cys1953Cys	synonymous	Exon 24 of 26	ENSP00000309555.7
HCFC1	ENST00000369984.4	TSL:5	c.5994C>T	p.Cys1998Cys	synonymous	Exon 24 of 26	ENSP00000359001.4
HCFC1	ENST00000444191.5	TSL:5	c.1584C>T	p.Cys528Cys	synonymous	Exon 8 of 10	ENSP00000399589.1

Frequencies

GnomAD3 genomes

AF:

0.415

AC:

46362

AN:

111821

Hom.:

9747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0854

Gnomad AMI

AF:

0.696

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.581

Gnomad EAS

AF:

0.00394

Gnomad SAS

AF:

0.125

Gnomad FIN

AF:

0.567

Gnomad MID

AF:

0.532

Gnomad NFE

AF:

0.644

Gnomad OTH

AF:

0.414

GnomAD2 exomes

AF:

0.426

AC:

75791

AN:

178057

AF XY:

0.434

show subpopulations

Gnomad AFR exome

AF:

0.0706

Gnomad AMR exome

AF:

0.204

Gnomad ASJ exome

AF:

0.557

Gnomad EAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.600

Gnomad NFE exome

AF:

0.648

Gnomad OTH exome

AF:

0.490

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.576

AC:

631434

AN:

1096360

Hom.:

136906

Cov.:

AF XY:

0.563

AC XY:

204100

AN XY:

362246

show subpopulations

African (AFR)

AF:

0.0743

AC:

1960

AN:

26385

American (AMR)

AF:

0.217

AC:

7627

AN:

35101

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

10605

AN:

19334

East Asian (EAS)

AF:

0.000696

AC:

AN:

30166

South Asian (SAS)

AF:

0.148

AC:

8017

AN:

54031

European-Finnish (FIN)

AF:

0.604

AC:

24067

AN:

39826

Middle Eastern (MID)

AF:

0.431

AC:

1762

AN:

4086

European-Non Finnish (NFE)

AF:

0.659

AC:

554089

AN:

841419

Other (OTH)

AF:

0.506

AC:

23286

AN:

46012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

9546

19091

28637

38182

47728

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16064

32128

48192

64256

80320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.414

AC:

46346

AN:

111874

Hom.:

9743

Cov.:

AF XY:

0.393

AC XY:

13393

AN XY:

34096

show subpopulations

African (AFR)

AF:

0.0852

AC:

2645

AN:

31040

American (AMR)

AF:

0.297

AC:

3176

AN:

10688

Ashkenazi Jewish (ASJ)

AF:

0.581

AC:

1535

AN:

2641

East Asian (EAS)

AF:

0.00395

AC:

AN:

3542

South Asian (SAS)

AF:

0.127

AC:

349

AN:

2758

European-Finnish (FIN)

AF:

0.567

AC:

3404

AN:

6000

Middle Eastern (MID)

AF:

0.535

AC:

115

AN:

215

European-Non Finnish (NFE)

AF:

0.644

AC:

34020

AN:

52794

Other (OTH)

AF:

0.407

AC:

619

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

691

1382

2073

2764

3455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

414

828

1242

1656

2070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.535

Hom.:

6466

Bravo

AF:

0.380

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Methylmalonic acidemia with homocystinuria, type cblX (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.26

(source)

DANN

Benign

0.58

PhyloP100

-0.40

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over